ORIGINAL CONTRIBUTION Neuropathologic Features of Amnestic Mild Cognitive Impairment Ronald C. Petersen, PhD, MD; Joseph E. Parisi, MD; Dennis W. Dickson, MD; Kris A. Johnson, RN; David S. Knopman, MD; Bradley F. Boeve, MD; Gregory A. Jicha, MD, PhD; Robert J. Ivnik, PhD; Glenn E. Smith, PhD; Eric G. Tangalos, MD; Heiko Braak, MD; Emre Kokmen, MD† Background: The neuropathologic substrate of amnes- Reagan criteria were used to analyze autopsy tissue from tic mild cognitive impairment (aMCI) is not known. 15 individuals who died while their clinical diagnosis was aMCI. For comparison, autopsy data on age-matched Objective: To determine the neuropathologic features groups of clinically healthy individuals and patients with of patients who died while their clinical classification was probable AD were analyzed. aMCI. Results: Most patients with aMCI did not meet the neu- Design: Cohort study. ropathologic criteria for AD, but their pathologic findings suggest a transitional state of evolving AD. All the patients Setting: Community based. with aMCI had pathologic findings involving medial tem- poral lobe structures, likely accounting for their memory Participants: Sixty-six individuals, including 15 who impairment. In addition, there were many concomitant had memory impairment beyond that allowed for aging pathologic abnormalities, including argyrophilic grain dis- but who were not demented, were studied along with 28 ease, hippocampal sclerosis, and vascular lesions. clinically healthy individuals and 23 patients with prob- able Alzheimer disease (AD) for comparison. Conclusions: The neuropathologic features of aMCI matched the clinical features and seemed to be interme- Main Outcome Measures: Standard neuropatho- diate between the neurofibrillary changes of aging and logic techniques and classification according to the pathologic features of very early AD. Khachaturian, Consortium to Establish a Registry for Alzheimer Disease, and National Institute on Aging– Arch Neurol. 2006;63:665-672 HE FIELD OF AGING AND DE- ment and likely progresses to AD, other sub- mentia is moving toward types, with different clinical criteria, have earlier identification of in- been proposed.10 One challenge in study- cipient disease states. The ing the transition between normal aging and concept of mild cognitive AD is the paucity of pathologic material on impairment (MCI) has evolved in recent patients with MCI. There are a few studies Author Affiliations: T years to represent the clinical transition be- in the literature on the neuropathologic fea- Alzheimer’s Disease Research tures of patients who are clinically mild and Center (Drs Petersen, Parisi, tween the cognitive changes found in nor- mal aging and those of early Alzheimer dis- very few on patients who died while their Dickson, Knopman, Boeve, 11-17 Jicha, Ivnik, Smith, Tangalos, ease (AD).1,2 Several international clinical clinical diagnosis was MCI. and Kokmen and Ms Johnson) trials3-5 evaluating a variety of interven- and Departments of Neurology tions for MCI have recently concluded. The For editorial comment (Drs Petersen, Knopman, American Academy of Neurology has en- Boeve, Jicha, and Kokmen), see page 645 Laboratory Medicine and dorsed the concept of MCI with an evi- Pathology (Dr Parisi), dence-based medicine practice param- The present study draws on a longitu- Neurosciences (Dr Dickson), eter paper highlighting the importance of dinal, community-based study of aging and Psychiatry and Psychology MCI as a clinical entity.6 dementia.2,18 Some members of this co- (Drs Ivnik and Smith), and There is debate in the field regarding the hort have been followed for up to 18 years. Internal Medicine specific clinical criteria, longitudinal out- Between September 1, 1986, and Decem- (Dr Tangalos), Mayo Clinic come, and underlying neuropathologic fea- ber 31, 2004, 15 patients died and under- College of Medicine, Rochester, tures of MCI.7-9 It has been recognized that Minn, and Jacksonville, Fla; and went autopsy while their clinical classifi- Institute for Clinical Anatomy, the concept of MCI may be heterog- cation was still aMCI. As such, this is one J.W. Goethe University, eneous, and although the most common of the first studies to characterize the neu- Frankfurt, Germany (Dr Braak). subtype, that is, amnestic MCI (aMCI), pre- ropathologic substrate of patients still in †Deceased. sents with prominent memory impair- the clinical state of aMCI. (REPRINTED) ARCH NEUROL / VOL 63, MAY 2006 WWW.ARCHNEUROL.COM 665 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 METHODS AUTOPSY PROCEDURE The brains were processed according to the protocol of the Mayo Alzheimer Disease Research Center Neuropathology Core. Af- CLINICAL EVALUATION ter external examination of the fresh specimen, the brain was divided by a sagittal cut into the right and left hemibrains. One During the past 18 years we followed more than 270 people hemisphere (usually the right) was serially sectioned into 1-cm who have received the diagnosis of MCI at some point in their coronal slabs, and alternate slices were frozen and fixed in para- clinical course. All were participants in the National Institute formaldehyde; the other hemisphere (usually the left) was fixed on Aging (NIA)–supported Mayo Clinic Alzheimer Disease for 7 to 10 days in 10% to 15% buffered formalin and was coro- Patient Registry.18 Participants were recruited prospectively in nally sectioned into 1-cm slabs and examined. The neuropatho- this project from primary care practices of the Division of logic protocol was performed according to the recommenda- Community Internal Medicine of the Mayo Clinic in Roches- tions of the Consortium to Establish a Registry for Alzheimer’s ter. The medical records of individuals 65 years and older Disease (CERAD)24 and the consensus guidelines for the clini- who had received a general medical examination were evalu- cal and pathological diagnosis of dementia with Lewy bodies.25 ated for any suggestion of a cognitive concern raised by the The following brain areas were routinely sampled: superior/ patient, a family member, or the examining physician. If a middle frontal gyri (plane just anterior to the temporal tip), su- concern was raised about cognitive function, permission was perior/middle temporal gyri (plane of the mammillary body), requested to approach the patient for evaluation. Patients then inferior parietal lobule (plane 1 cm behind the posterior pole underwent neurologic evaluation and neuropsychologic test- of the splenium), calcarine (primary visual) cortex, anterior cin- ing, neuroimaging, and laboratory studies. These studies have gulate (plane of the anterior commissure), hippocampus with been approved by the Mayo institutional review board. adjacent inferior temporal cortex (level of the lateral genicu- Patients were diagnosed as having aMCI if they fulfilled late body), amygdala and entorhinal cortex (level of the mam- the following criteria: (1) memory concerns, usually by the millary bodies), nucleus basalis, basal ganglia, cerebellum, thala- patient, preferably corroborated by an informant, (2) objective mus with subthalamic nucleus, midbrain (with substantia nigra), memory impairment for age, (3) essentially normal general pons (with locus ceruleus), and cerebellum, as well as repre- cognitive function as judged by the physician, (4) normal sentative sections of any lesions noted grossly. activities of daily living as judged by the physician, and (5) After routine processing in paraffin and cutting, sections were not demented. The diagnosis was made on a clinical basis; stained with hematoxylin-eosin, and selected sections were that is, a consensus committee comprising neurologists, a stained with modified Bielschowsky, Luxol fast blue/periodic geriatrician, neuropsychologists, nurses, and other study per- acid–Schiff, and thioflavin-S and immunostained for ␤-amy- sonnel adjudicated each case. Specific neuropsychologic cut- loid (clone 6F/3D) (Novocastra Laboratories Ltd, Newcastle off scores were not used; instead, the patients were diagnosed upon Tyne, England), phosphorylated tau (clone AT8) (En- as having aMCI if their memory performance was impaired dogen, Woburn, Mass), ␣-synuclein (clone LB509) (Zymed out of proportion to their other cognitive domains.2,10 These Laboratories, San Francisco, Calif), ubiquitin (polyclonal) individuals may have had isolated memory impairments (Dako, Glostrup, Denmark), neurofilament protein (clone 2F11) (single-domain aMCI) or may have mild impairments in non- (Dako), ␣-␤-crystallin (polyclonal) (Chemicon International memory domains (multiple-domain aMCI). Their activities of Inc, Temecula, Calif), and glial fibrillary acidic protein (poly- daily living were essentially intact except for some of the clonal) (Dako). minor impairments related to the memory disorder as docu- mented by the Record of Independent Living and the Clinical Dementia Rating scale.19,20 NEUROPATHOLOGIC ASSESSMENT After initial assessment and enrollment, patients were reevaluated annually. At each reevaluation they were Regions in which the counting was performed were selected assessed clinically, and their performance was reviewed at macroscopically, according to the method of Duyckaerts et al,26 the consensus conference. The consensus conference com- as the areas of the slide where the cortical ribbon was the thin- mittee determined whether the patient continued to fulfill nest (ie, where the angle of section was the closest to